Greater than 90% of all therapeutic compounds are administered via the oral route, of which the tablet dosage form is by far the most popular. The quality of this solid oral dosage form is, as a general rule, primarily governed by the physical and chemical properties of the granulation from which the tablets are composed.
It is particularly important in the granulation process to be able to control the granules size distribution, shape and surface characteristics. These granule characteristics in turn affect the formulation design and manufacture of tablets and capsules as well as impacting the bioavailability of the active pharmaceutical components in the granules.
Many techniques are known for preparing granulations from powdered materials such as wet granulation, solvent granulation and melt granulation. All of these techniques involve the addition of an inactive binder to aggregate smaller particles into larger granules. For example, wet granulation and solvent granulation require the addition of a liquid binder which aggregates the active materials and excipients into granules. After granulation, the liquid generally must be removed by a separate drying step. Melt granulation is similar to wet granulation, but uses a low melting point solid material as a binder. The solid binder in melt granulation is melted and acts as a liquid binder thereby aggregating the powdered active material and excipients into granules. The binder thereby, is permanently incorporated into the granules when the granules cool.
Each of these granulation techniques has drawbacks. Wet granulation requires a liquid be added which requires tanks and handling equipments. Since the liquid used in wet granulation must subsequently be removed, a drying step is also needed which requires drying equipment and further complicates the manufacturing process. Additionally, wet granulation is not well suited to making granules which incorporate water absorbing disintegrants. Unless the wet granulation is very carefully controlled the water absorbing disintegrant will absorb the water as it is added to the granulation and result in a swollen mass being formed instead of discreet granules. To solve this problem and avoid the inactivation of water sensitive pharmaceuticals a solvent based granulation can be used. The solvent used in this granulation process is generally a volatile hydrocarbon or alcohol which can easily be removed from the granules after they are formed. Since water is not involved in this granulation process the problems with the incorporation of disintegrants and inactivation of pharmaceuticals is avoided. However, the use of highly volatile solvents present a new set of problems. The foremost problem with solvent granulation is the risk of explosion which can occur any time one is handling volatile solvents. Special precaution are necessary to avoid explosions and protect worker from exposure to these solvents.
Melt granulation on the other hand avoids the problems associated with adding liquids by incorporating a low melting solid binder. The low melting point binder must be heated to at least its softening point and melted during the granulation process. The heat necessary to soften or melt the binder is generally supplied by a high shear mixing device. Unfortunately, it is difficult to control the heat distribution generated by high shear mixing which may result in heat inactivation of some active materials. Another significant problem with melt granulation with high shear mixing is that the granules formed have a broad distribution of granule sizes and tend to be fragile. These characteristics make the granules difficult to handle in subsequent processing into tablets and capsules and significantly contribute to product waste.
Thus, it would be a significant advancement to the art if a new process for granulation could be developed.